CORRESPONDENCE: RESEARCH CORRESPONDENCE
Left Ventricular Apical Ballooning Syndrome as a Novel Cause of Acute Mitral Regurgitation
Guido Parodi, MD, PhD, FESC*,
Stefano Del Pace, MD,
Claudia Salvadori, MD,
Nazario Carrabba, MD,
Iacopo Olivotto, MD,
Gian Franco Gensini, MD for the Tuscany Registry of Tako-Tsubo Cardiomyopathy
* Division of Cardiology, Careggi Hospital, Viale Morgagni 85, I-50134 Florence, Italy (Email: parodiguido{at}libero.it).
To the Editor: Transient left ventricular apical ballooning syndrome (LVABS), also known as Tako-Tsubo or stress-induced cardiomyopathy, is a recently described clinical condition, largely confined to female gender, that may mimic acute myocardial infarction. It is characterized by chest pain, ischemic electrocardiographic changes, transient wall motion abnormalities mainly in the midapical segments, and limited release of cardiac injury markers in the absence of obstructive coronary disease (1–4). The syndrome generally has a favorable outcome (2–4); however, occasional complications may occur. One possible, and potentially serious, complication is acute clinically significant mitral regurgitation (MR). We sought to evaluate the incidence, clinical findings, and outcome associated with acute MR in patients with LVABS.
The study comprised patients consecutively admitted to our institution for chest pain or dyspnoea who met the diagnostic criteria for LVABS (2). Specifically, patients with angiographic evidence of significant coronary stenosis, plaque rupture, thrombosis, or spasm of major epicardial coronary arteries were excluded from the present registry.
Mitral regurgitation was graded as mild, moderate, moderate-to-severe, or severe, based on a multiparametric Doppler evaluation, including measurement of the vena contracta, maximal regurgitant area-to-left atrial area ratio, and grading (1 to 4) of color flow imaging with parasternal and apical views. It was considered clinically significant when moderate-to-severe or severe (i.e., with maximal area-to-left atrial of area ratio >50% in the apical view, and a vena contracta >6 mm in the parasternal long-axis or apical view).
Continuous data were expressed as mean ± standard deviation and categorical data as proportions (%). Comparisons were performed with the chi-square test and unpaired t test, as appropriate. Forward stepwise multiple logistic regression analysis was used to identify independent predictors of Killip class III to IV on admission and of acute MR. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated. A value of p < 0.05 was considered statistically significant. Statistical analysis was performed with SPSS 11.5 for Windows (SPSS Inc., Chicago, Illinois).
From July 2003 to September 2006, 68 consecutive patients with LVABS were prospectively included in the study (Table 1). Of note, 4 patients (6%) were men. In the majority of patients (72%), antecedent emotional or physical stressors triggering LVABS was identified. Fourteen patients (21%) presented in Killip class III to IV. Urgent angiography did not show significant coronary artery disease in any of the patients. Specifically, 54 patients (79%) had truly normal coronary arteries, whereas 14 (21%) had subcritical coronary stenoses (<50%) randomly located in the coronary tree.
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Table 1 Baseline Clinical and Echographic Characteristics of Patients With and Without Significant Acute Mitral Regurgitation
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On presentation, 14 of the 68 patients (21%) had significant (moderate-to-severe or severe) acute MR (Fig. 1). None were males. Patients with MR more often presented with pulmonary edema or cardiogenic shock (Table 1). Indeed, echocardiographic MR grade was the only predictor of Killip class III to IV on admission (HR 2.24, 95% CI 1.11 to 4.50, p = 0.024).
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Figure 1 Severe Acute Mitral Regurgitation Due to Left Ventricular Apical Ballooning Syndrome
Biplane 30° right oblique contrast left ventriculographic projection of 2 patients with left ventricular apical ballooning syndrome and severe mitral regurgitation (systolic frame). The typical wall motion abnormality pattern is characterized by "ballooning" of the midapical segments and hyperkinesia of the basal segments. The resulting mitral regurgitation is massive with contrast media spread in the left atrium and pulmonary veins. LA = left atrium; LV = left ventricle.
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All the 14 patients had significant papillary muscle displacement and leaflet tethering, impairing coaptation. In addition, 5 patients with MR had mitral systolic anterior motion (SAM), associated with dynamic left ventricular (LV) outflow tract obstruction, contributing significantly to the degree of MR. These 5 patients had peak systolic LV outflow gradients ranging from 43 to 100 mm Hg; 3 had grade 3 to 4+ SAM, with mitral septal contact. Significant mitral valve leaflet sclerosis was present in only 4 of the 14 patients with MR (29%), and none showed mitral valve annulus dilation.
Of note, patients with MR had significantly more depressed left ventricular ejection fraction (LVEF) on admission (Table 1). At multivariate analysis, EF on admission (HR 0.85, 95% CI 0.75 to 0.96, p = 0.009) and mitral SAM (HR 18.00, 95% CI 1.63 to 98.51, p = 0.018) were the only independent predictors of acute MR. There was no difference in the prevalence of coronary stenosis <50% between patients with and without acute MR (29% vs. 19%; p = NS).
Predischarge LVEF was lower in the MR group, and LV function normalization was delayed (Table 1). Early improvement of MR grade was observed in 11 of the 14 MR patients (79%); of the remaining 3 patients, 2 showed no improvement and died while in the hospital and 1 improved to mild-to-moderate MR at 1 month follow-up. At discharge, no patient had evidence of residual LV outflow tract obstruction caused by SAM.
No patient died during hospitalization in the group without MR. Conversely, two 85-year-old women with severe LV dysfunction and MR died as the result of refractory cardiogenic shock and refractory heart failure associated with pneumonia, respectively. Follow-up was 9 ± 6 months. An 83-year-old woman without MR died of sepsis 7 months after hospitalization. Thus, overall mortality rates in patients with and without acute MR were 14% and 2%, respectively (p = 0.044). No patient experienced LVABS recurrence during follow-up, and there was no difference in rehospitalization rate between patients with and without acute MR (9% vs. 8%; p = 0.911).
Left ventricular apical ballooning syndrome comprises 2% of patients admitted for suspicion of ST-segment elevation acute myocardial infarction (4) and should therefore not be considered unusual in clinical practice. The syndrome has only recently been described and remains largely unexplored in its entire spectrum of clinical and pathophysiological manifestations. In our cohort of 68 consecutive, largely female patients with LVABS, 21% showed moderate-to-severe or severe MR, which could largely be characterized as functional and non–pre-existing, in that it disappeared or became substantially milder after recovery of LV morphology and function.
Despite the generally benign nature of LVABS (2,4), the associated presence of significant acute MR identified a subset of patients at increased risk of acute deterioration and adverse outcome. Indeed, MR represented the hallmark of the more severe end of LVABS spectrum, occurring preferentially in patients with the lowest LVEF values. The combination of volume overload caused by MR with severe LV dysfunction was a potent predictor of hemodynamic derangement leading to hazardous clinical manifestations, including pulmonary edema and cardiogenic shock. Furthermore, patients with acute MR showed less complete and slower recovery of LV function, occasionally associated with persistence of substantial regurgitation during follow-up.
The mechanism of acute MR during LVABS is likely due to complex and multiple mechanisms. Nevertheless, the main factor involved seems to lie in the altered spatial relationship between mitral leaflets and the subvalvular apparatus, caused by the apical ballooning. Indeed, papillary muscle displacement was a constant finding in all our patients with acute MR, leading to impaired leaflet coaptation secondary to tethering. In addition, SAM occurred in 36% of patients with MR and appeared to play a relevant role in determining the presence and degree of regurgitation during the acute phase of LVABS, as well as causing significant LV outflow obstruction (5). It is well known from studies on hypertrophic cardiomyopathy that SAM is almost constantly associated with variable degrees of MR, which may be severe (6,7). In patients with LVABS, SAM may originate from the combination of apical ballooning and distortion of the LV, abnormal papillary muscle tethering forces, mitral valve displacement, and proximity of midapical bulging and akynesia with hypercontractile basal LV segments (5).
In addition, we cannot exclude the contribution of other mechanisms to acute MR, such as reduced papillary muscle contraction and absolute or relative decrease in LV preload. Conversely, a key role for mitral annulus dilation and structural leaflet abnormalities seems unlikely based on our findings. Finally, significant mitral leaflet sclerosis was found in the small number of patients with delayed or absent improvement of MR. This finding suggests that pre-existing degrees of valve degeneration or other structural abnormalities may be relevant in determining the extent and time-course of MR and its recovery in LVABS.
These observations imply that acute MR should be actively sought and carefully evaluated in patients with LVABS, as a potential marker of adverse clinical course requiring aggressive treatment. Likewise, LVABS should be systematically considered in the differential diagnosis of patients admitted for heart failure or cardiogenic shock associated with acute MR.
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1. Kurisu S, Sato H, Kawagoe T, et al. Tako-tsubo-like left ventricular dysfunction with ST-segment elevation: a novel cardiac syndrome mimicking acute myocardial infarction Am Heart J 2002;143:448-455.[CrossRef][Web of Science][Medline]2. Bybee KA, Kara T, Prasad A, et al. Transient left ventricular apical ballooning: a syndrome that mimics ST-segment elevation myocardial infarction Ann Intern Med 2004;141:858-865.[Abstract/Free Full Text] 3. Sharkey SW, Lesser JR, Zenovich AG, et al. Acute and reversible cardiomyopathy provoked by stress in women from the United States Circulation 2005;111:472-479.[Abstract/Free Full Text] 4. Parodi G, Del Pace S, Carrabba N, et al. Incidence, clinical findings and outcome of women with left ventricular apical ballooning syndrome Am J Cardiol 2007;99:182-185.[CrossRef][Web of Science][Medline] 5. Levine RA, Vlahakes GJ, Lefebvre X, et al. Papillary muscle displacement causes systolic anterior motion of the mitral valve: experimental validation and insights into the mechanism of subaortic obstruction Circulation 1995;91:1189-1195.[Abstract/Free Full Text] 6. Schwammenthal E, Nakatani S, He S, et al. Mechanism of mitral regurgitation in hypertrophic cardiomyopathy: mismatch of posterior to anterior leaflet length and mobility Circulation 1998;98:856-865.[Abstract/Free Full Text] 7. Maron MS, Olivotto I, Zenovich AG, et al. Hypertrophic cardiomyopathy is predominantly a disease of left ventricular outflow tract obstruction Circulation 2006;114:2232-2239.[Abstract/Free Full Text]
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